tbuckley/cabot-search huggingface dataset:
Integrating single-cell and spatial transcriptomics reveals endoplasmic reticulum stress-related CAF subpopulations associated with chordoma progression
Authors: Tao-Lan Zhang, Chao Xia, Bo-Wen Zheng, Hai-Hong Hu, Ling-Xiang Jiang, David Escobar, Bo-Yv Zheng, Tian-Dong Chen, Jing Li, Guo-Hua Lv, Wei Huang, Yi-Guo Yan, Ming-Xiang Zou
Journal: Neuro-Oncology (2023)

Abstract Background With cancer-associated fibroblasts (CAFs) as the main cell type, the rich myxoid stromal components in chordoma tissues may likely contribute to its development and progression. Methods Single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, bulk RNA-seq, and multiplexed quantitative immunofluorescence (QIF) were used to dissect the heterogeneity, spatial distribution, and clinical implication of CAFs in chordoma. Results We sequenced here 72 097 single cells from 3 primary and 3 recurrent tumor samples, as well as 3 nucleus pulposus samples as controls using scRNA-seq. We identified a unique cluster of CAF in recurrent tumors that highly expressed hypoxic genes and was functionally enriched in endoplasmic reticulum stress (ERS). Pseudotime trajectory and cell communication analyses showed that this ERS-CAF subpopulation originated from normal fibroblasts and widely interacted with tumoral and immune cells. Analyzing the bulk RNA-seq data from 126 patients, we found that the ERS-CAF signature score was associated with the invasion and poor prognosis of chordoma. By integrating the results of scRNA-seq with spatial transcriptomics, we demonstrated the existence of ERS-CAF in chordoma tissues and revealed that this CAF subtype displayed the most proximity to its surrounding tumor cells. In subsequent QIF validation involving 105 additional patients, we confirmed that ERS-CAF was abundant in the chordoma microenvironment and located close to tumor cells. Furthermore, both ERS-CAF density and its distance to tumor cells were correlated with tumor malignant phenotype and adverse patient outcomes. Conclusions These findings depict the CAF landscape for chordoma and may provide insights into the development of novel treatment approaches.
Targeting galectin-3 in myocardial infarction: a unique opportunity for biomarker-guided therapy
Authors: Nikolaos G Frangogiannis
Journal: Cardiovascular Research (2023)

Could galectin-3 inhibition perturb repair of the infarcted heart?Considering the central role of fibroblasts in repair of the infarcted heart, implementation of anti-fibrotic strategies in myocardial infarction mayThe opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.
Calcium channel blocker use and outcomes in patients with heart failure and mildly reduced and preserved ejection fraction
Authors: Shingo Matsumoto, Toru Kondo, Mingming Yang, Ross T. Campbell, Kieran F. Docherty, Rudolf A. de Boer, Akshay S. Desai, Carolyn S.P. Lam, Milton Packer, Bertram Pitt, Jean L. Rouleau, Muthiah Vaduganathan, Faiez Zannad, Michael R. Zile, Scott D. Solomon, Pardeep S. Jhund, John J.V. McMurray
Journal: European Journal of Heart Failure (2023)
Epitope-engineered human hematopoietic stem cells are shielded from CD123-targeted immunotherapy
Authors: Romina Marone, Emmanuelle Landmann, Anna Devaux, Rosalba Lepore, Denis Seyres, Jessica Zuin, Thomas Burgold, Corinne Engdahl, Giuseppina Capoferri, Alessandro Dell’Aglio, Clément Larrue, Federico Simonetta, Julia Rositzka, Manuel Rhiel, Geoffroy Andrieux, Danielle N. Gallagher, Markus S. Schröder, Amélie Wiederkehr, Alessandro Sinopoli, Valentin Do Sacramento, Anna Haydn, Laura Garcia-Prat, Christopher Divsalar, Anna Camus, Liwen Xu, Lorenza Bordoli, Torsten Schwede, Matthew Porteus, Jérôme Tamburini, Jacob E. Corn, Toni Cathomen, Tatjana I. Cornu, Stefanie Urlinger, Lukas T. Jeker
Journal: The Journal of Experimental Medicine (2023)

Targeted eradication of transformed or otherwise dysregulated cells using monoclonal antibodies (mAb), antibody–drug conjugates (ADC), T cell engagers (TCE), or chimeric antigen receptor (CAR) cells is very effective for hematologic diseases. Unlike the breakthrough progress achieved for B cell malignancies, there is a pressing need to find suitable antigens for myeloid malignancies. CD123, the interleukin-3 (IL-3) receptor alpha-chain, is highly expressed in various hematological malignancies, including acute myeloid leukemia (AML). However, shared CD123 expression on healthy hematopoietic stem and progenitor cells (HSPCs) bears the risk for myelotoxicity. We demonstrate that epitope-engineered HSPCs were shielded from CD123-targeted immunotherapy but remained functional, while CD123-deficient HSPCs displayed a competitive disadvantage. Transplantation of genome-edited HSPCs could enable tumor-selective targeted immunotherapy while rebuilding a fully functional hematopoietic system. We envision that this approach is broadly applicable to other targets and cells, could render hitherto undruggable targets accessible to immunotherapy, and will allow continued posttransplant therapy, for instance, to treat minimal residual disease (MRD).
Granularity in disease classification impacts survival prediction in advanced systemic mastocytosis: A single institution study of 329 informative cases
Authors: Ayalew Tefferi, Maymona Abdelmagid, Aref Al‐Kali, Mrinal Patnaik, William J. Hogan, Kebede Begna, Naseema Gangat, Attilio Orazi, Dong Chen, Kaaren K. Reichard, Animesh Pardanani
Journal: American Journal of Hematology (2023)

Abstract The World Health Organization (WHO) classification system categorizes advanced systemic mastocytosis (SM‐Adv) into aggressive SM (ASM), mast cell leukemia (MCL), and SM with associated hematological neoplasm (SM‐AHN). By contrast, the International Consensus Classification (ICC) requires “immature” MC cytomorphology for the diagnosis of MCL and limits SM‐AHN to myeloid neoplasms (SM‐AMN). The current study includes 329 patients with SM‐Adv (median age 65 years, range 18–88; males 58%): WHO subcategories SM‐AHN ( N = 212; 64%), ASM ( N = 99; 30%), and MCL ( N = 18; 6%); ICC subcategories SM‐AMN ( N = 190; 64%), ASM (N = 99; 33%), and MCL ( N = 9; 3%); WHO‐defined MCL with “mature” MC cytomorphology and SM‐AHN associated with lymphoid neoplasms were operationally labeled as “MCL‐mature” ( N = 9) and SM‐ALN ( N = 22), respectively, and distinguished from ICC‐defined MCL and SM‐AMN. Multivariable analysis that included the Mayo alliance risk factors for survival in SM (age &gt;60 years, anemia, thrombocytopenia, increased alkaline phosphatase) revealed more accurate survival prediction with the ICC versus WHO classification order: (i) survival was significantly worse with MCL‐immature versus MCL‐mature (hazard ratio [HR] 15; p &lt; .01), (ii) prognostic distinction between MCL and SM‐AHN/AMN was confirmed in the context of ICC (HR 9.3; p &lt; .01) but not WHO classification order ( p = .99), (iii) survival was similar between MCL‐mature and SM‐AMN ( p = .18), and (iv) SM‐AMN (HR 1.7; p &lt; .01) but not SM‐ALN ( p = .37) was prognostically distinct from ASM. The current study provides evidence for the independent prognostic contribution of both the ICC system for SM‐Adv and the Mayo alliance risk factors for survival in SM.
Clinical Behavior and Molecular Landscape of Stage I p53-Abnormal Low-Grade Endometrioid Endometrial Carcinomas
Authors: Amy Jamieson, Lisa Vermij, Claire J.H. Kramer, Jan J. Jobsen, Ina Jürgemlienk-Schulz, Ludy Lutgens, Jan Willem Mens, Marie A.D. Haverkort, Annerie Slot, Remi A. Nout, Jan Oosting, Joseph Carlson, Brooke E. Howitt, Philip P.C. Ip, Sigurd F. Lax, W. Glenn McCluggage, Naveena Singh, Jessica N. McAlpine, Carien L. Creutzberg, Nanda Horeweg, C. Blake Gilks, Tjalling Bosse
Journal: Clinical Cancer Research (2023)

Abstract Purpose: The clinical significance of the p53-abnormal (p53abn) molecular subtype in stage I low-grade endometrioid endometrial carcinoma (EEC) is debated. We aimed to review pathologic and molecular characteristics, and outcomes of stage I low-grade p53abn EEC in a large international cohort. Experimental Design: Previously diagnosed stage I p53abn EC (POLE–wild-type, mismatch repair–proficient) low-grade EEC from Canadian retrospective cohorts and PORTEC-1&amp;2 trials were included. Pathology review was performed by six expert gynecologic pathologists blinded to p53 status. IHC profiling, next-generation sequencing, and shallow whole-genome sequencing was performed. Kaplan–Meier method was used for survival analysis. Results: We identified 55 stage I p53abn low-grade EEC among 3,387 cases (2.5%). On pathology review, 17 cases (31%) were not diagnosed as low-grade EEC by any pathologists, whereas 26 cases (47%) were diagnosed as low-grade EEC by at least three pathologists. The IHC and molecular profile of the latter cases were consistent with low-grade EEC morphology (ER/PR positivity, patchy p16 expression, PIK3CA and PTEN mutations) but they also showed features of p53abn EC (TP53 mutations, many copy-number alterations). These cases had a clinically relevant risk of disease recurrence (5-year recurrence-free survival 77%), with pelvic and/or distant recurrences observed in 12% of the patients. Conclusions: A subset of p53abn EC is morphologically low-grade EEC and exhibit genomic instability. Even for stage I disease, p53abn low-grade EEC are at substantial risk of disease recurrence. These findings highlight the clinical relevance of universal p53-testing, even in low-grade EEC, to identify women at increased risk of recurrence.
Lipid Nanoparticle Delivery Alters the Adjuvanticity of the TLR9 Agonist CpG by Innate Immune Activation in Lymphoid Tissue
Authors: Zifu Zhong, Yong Chen, Kim Deswarte, Heleen Lauwers, Emily De Lombaerde, Xiaole Cui, Simon Van Herck, Tingting Ye, Mark Gontsarik, Stefan Lienenklaus, Niek N. Sanders, Bart N. Lambrecht, Stefaan De Koker, Bruno G. De Geest
Journal: Advanced Healthcare Materials (2023)

Abstract Pharmacological strategies to activate innate immune cells are of great relevance in the context of vaccine design and anticancer immune therapy, to mount broad immune responses able to clear infection and malignant cells. Synthetic CpG oligodeoxynucleotides (CpG‐ODNs) are short single‐stranded DNA molecules containing unmethylated CpG dinucleotides and a phosphorothioate backbone. Class B CpG ODNs activate robust innate immune responses through a TLR9‐dependent NF‐κB signaling pathway. This feature is attractive to exploit in the context of vaccine design and cancer immunotherapy. Soluble CpG‐ODNs cause hepatic toxicity, which reduces its therapeutic applicability. The formulation of class B CpG ODN1826 in lipid nanoparticles (LNPs) containing an ionizable cationic lipid that complexes CpG through electrostatic interaction is reported. Upon local administration, LNP‐formulated CpG drains to lymph nodes and triggers robust innate immune activation. Unformulated, soluble, CpG, by contrast, is unable to induce robust innate activation in draining lymph nodes and is distributed systemically. In a vaccination setting, LNP‐formulated CpG, admixed with a protein antigen, induces higher antigen‐specific antibody titers and T cell responses than antigen admixed with unformulated soluble CpG.
An Anterior Second Heart Field Enhancer Regulates the Gene Regulatory Network of the Cardiac Outflow Tract
Authors: Naoko Yamaguchi, Ernest W. Chang, Ziyan Lin, Akshay Shekhar, Lei Bu, Alireza Khodadadi-Jamayran, Aristotelis Tsirigos, Yiyun Cen, Colin K.L. Phoon, Ivan P. Moskowitz, David S. Park
Journal: Circulation (2023)

Conotruncal defects due to developmental abnormalities of the outflow tract (OFT) are an important cause of cyanotic congenital heart disease. Dysregulation of transcriptional programs tuned by NKX2-5 (NK2 homeobox 5), GATA6 (GATA binding protein 6), and TBX1 (T-box transcription factor 1) have been implicated in abnormal OFT morphogenesis. However, there remains no consensus on how these transcriptional programs function in a unified gene regulatory network within the OFT.
Treatment of IgA Nephropathy: A Rapidly Evolving Field
Authors: Khalil El Karoui, Fernando C. Fervenza, An S. De Vriese
Journal: Journal of the American Society of Nephrology (2023)

The pivotal event in the pathophysiology of IgA nephropathy is the binding of circulating IgA-containing immune complexes to mesangial cells, with secondary glomerular and tubulointerstitial inflammation and fibrosis. The paramount difficulty in the management of IgA nephropathy is the heterogeneity in its clinical presentation and prognosis, requiring an individualized treatment approach. Goal-directed supportive care remains the bedrock of therapy for all patients, regardless of risk of progression. Sodium–glucose transporter 2 inhibitors and sparsentan should be integral to contemporary supportive care, particularly in patients with chronic kidney damage. Pending the development of reliable biomarkers, it remains a challenge to identify patients prone to progression due to active disease and most likely to derive a net benefit from immunosuppression. The use of clinical parameters, including the degree of proteinuria, the presence of persistent microscopic hematuria, and the rate of eGFR loss, combined with the mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, crescents score, is currently the best approach. Systemic glucocorticoids are indicated in high-risk patients, but the beneficial effects wane after withdrawal and come at the price of substantial treatment-associated toxicity. Therapies with direct effect on disease pathogenesis are increasingly becoming available. While targeted-release budesonide has garnered the most attention, anti–B-cell strategies and selective complement inhibition will most likely prove their added value. We propose a comprehensive approach that tackles the different targets in the pathophysiology of IgA nephropathy according to their relevance in the individual patient.
Olaparib and Ceralasertib (AZD6738) in Patients with Triple-Negative Advanced Breast Cancer: Results from Cohort E of the plasmaMATCH Trial (CRUK/15/010)
Authors: Alistair Ring, Lucy S. Kilburn, Alex Pearson, Laura Moretti, Angelica Afshari-Mehr, Andrew M. Wardley, Bora Gurel, Iain R. Macpherson, Ruth Riisnaes, Richard D. Baird, Sue Martin, Rebecca Roylance, Hannah Johnson, Ana Ferreira, Matthew C. Winter, Kathryn Dunne, Ellen Copson, Tamas Hickish, Russell Burcombe, Kat Randle, Violeta Serra, Alba Llop-Guevara, Judith M. Bliss, Nicolas C. Turner
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Approximately 10% to 15% of triple-negative breast cancers (TNBC) have deleterious mutations in BRCA1 and BRCA2 and may benefit from PARP inhibitor treatment. PARP inhibitors may also increase exogenous replication stress and thereby increase sensitivity to inhibitors of ataxia telangiectasia and Rad3-related (ATR) protein. This phase II study examined the activity of the combination of PARP inhibitor, olaparib, and ATR inhibitor, ceralasertib (AZD6738), in patients with advanced TNBC. Patients and Methods: Patients with TNBC on most recent biopsy who had received 1 or 2 lines of chemotherapy for advanced disease or had relapsed within 12 months of (neo)adjuvant chemotherapy were eligible. Treatment was olaparib 300 mg twice a day continuously and celarasertib 160 mg on days 1–7 on a 28-day cycle until disease progression. The primary endpoint was confirmed objective response rate (ORR). Tissue and plasma biomarker analyses were preplanned to identify predictors of response. Results: 70 evaluable patients were enrolled. Germline BRCA1/2 mutations were present in 10 (14%) patients and 3 (4%) patients had somatic BRCA mutations. The confirmed ORR was 12/70; 17.1% (95% confidence interval, 10.4–25.5). Responses were observed in patients without germline or somatic BRCA1/2 mutations, including patients with mutations in other homologous recombination repair genes and tumors with functional homologous recombination deficiency by RAD51 foci. Conclusions: The response rate to olaparib and ceralasertib did not meet prespecified criteria for activity in the overall evaluable population, but responses were observed in patients who would not be expected to respond to olaparib monotherapy.
RETRACTED: A predictive model of herpes zoster after allogeneic hematopoietic stem cell transplantation: <scp>VZV</scp> reactivation following antiviral prophylaxis discontinuation
Authors: Cheng‐Jie Feng, Peng Zhao, Hai‐Xia Fu, Chen‐Hua Yan, Chen‐Cong Wang, Xiao‐Lu Zhu, Yun He, Feng‐Rong Wang, Yuan‐Yuan Zhang, Xiao‐Dong Mo, Yuan Kong, Wei Han, Jing‐Zhi Wang, Yu Wang, Huan Chen, Yu‐Hong Chen, Xiang‐Yu Zhao, Ying‐Jun Chang, Lan‐Ping Xu, Kai‐Yan Liu, Xiao‐Jun Huang, Xiao‐Hui Zhang
Journal: American Journal of Hematology (2023)

Abstract Herpes zoster (HZ) refers to the rash appearing on dermatomes due to varicella zoster virus (VZV) reactivation. The incidence of HZ is significantly higher in allogeneic hematopoietic stem cell transplantation (allo‐HSCT) recipients than in non‐HSCT recipients. Although acyclovir prophylaxis is routinely administered to every allo‐HSCT recipient for 1 year after transplantation, some individuals eventually develop late‐onset HZ after completing prophylaxis. Little information is known about the clinical features of HZ after prophylactic antiviral treatment discontinuation, and an effective predictive model of late‐onset HZ needs to be established. A total of 3366 patients who had received allo‐HSCT from 2012 to 2017 were included in our study, among whom 201 developed HZ after 1 year (late‐onset HZ). We designed a nested case–control study to identify potential predictors of late‐onset HZ. Finally, we established a predictive model using binary logistic regression analysis. Age ( p &lt; .001), use of immunosuppressants at +1 year ( p &lt; .001), CD4‐CD8 ratio at +1 year ( p &lt; .001), certain mental disorders (depression, anxiety, insomnia and adjustment disorder) (p &lt; .001), engraftment time of neutrophils ( p &lt; .001), and CD8 + cell count at +30 days ( p &lt; .001) were independent predictors of late‐onset HZ. A risk grading system was established based on regression coefficients. Discrimination and calibration analysis indicated that the model had good performance. We also identified several predictive factors of the incidence of HZ‐related complications. This is the first scoring system for predicting the incidence of late‐onset HZ after allo‐HSCT. This model can be applied to identify individuals at high risk of late‐onset HZ in the early period after receiving allo‐HSCT.
Integrative medicine and self-care in the treatment of lymphatic filariasis-associated lymphoedema: an effective strategy!
Authors: Archana Singal, Kavita Bisherwal
Journal: British Journal of Dermatology (2023)

Journal Article Corrected proof Integrative medicine and self-care in the treatment of lymphatic filariasis-associated lymphoedema: an effective strategy! Get access Archana Singal, Archana Singal Conceptualization, Writing - original draft, Writing - review & editing Department of Dermatology and STD, University College of Medical Sciences and GTB Hospital, University of Delhi, New Delhi, India Correspondence: Archana Singal. Email: archanasingal@gmail.com https://orcid.org/0000-0001-9201-3391 Search for other works by this author on: Oxford Academic Google Scholar Kavita Bisherwal Kavita Bisherwal Conceptualization, Writing - original draft, Writing - review & editing Department of Dermatology and STD, University College of Medical Sciences and GTB Hospital, University of Delhi, New Delhi, India https://orcid.org/0000-0002-7415-9802 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, ljad374, https://doi.org/10.1093/bjd/ljad374 Published: 29 September 2023 Article history Received: 19 September 2023 Accepted: 21 September 2023 Published: 29 September 2023 Corrected and typeset: 02 November 2023
Treatment of Systemic Sclerosis–associated Interstitial Lung Disease: Evidence-based Recommendations. An Official American Thoracic Society Clinical Practice Guideline
Authors: Ganesh Raghu, Sydney B. Montesi, Richard M. Silver, Tanzib Hossain, Madalina Macrea, Derrick Herman, Hayley Barnes, Ayodeji Adegunsoye, Arata Azuma, Lorinda Chung, Gregory C. Gardner, Kristin B. Highland, Marie Hudson, Robert J. Kaner, Martin Kolb, Mary Beth Scholand, Virginia Steen, Carey C. Thomson, Elizabeth R. Volkmann, Fredrick M. Wigley, Dee Burlile, Karen A. Kemper, Shandra L. Knight, Marya Ghazipura
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Interstitial lung disease (ILD) is a significant cause of morbidity and mortality in patients with systemic sclerosis (SSc). To date, clinical practice guidelines regarding treatment for patients with SSc-ILD are primarily consensus based.
happi: a hierarchical approach to pangenomics inference
Authors: Pauline Trinh, David S. Clausen, Amy D. Willis
Journal: Genome biology (2023)

Abstract Recovering metagenome-assembled genomes (MAGs) from shotgun sequencing data is an increasingly common task in microbiome studies, as MAGs provide deeper insight into the functional potential of both culturable and non-culturable microorganisms. However, metagenome-assembled genomes vary in quality and may contain omissions and contamination. These errors present challenges for detecting genes and comparing gene enrichment across sample types. To address this, we propose , an approach to testing hypotheses about gene enrichment that accounts for genome quality. We illustrate the advantages of over existing approaches using published Saccharibacteria MAGs, Streptococcus thermophilus MAGs, and via simulation.
For whom the B(c)ell tolls: CXCL4 AIDs human autoimmunity
Authors: Stuart G. Tangye
Journal: The Journal of Experimental Medicine (2023)

In this issue of JEM, Çakan et al. (2023. J. Exp. Med.https://doi.org/10.1084/jem.20230944) explore a CXCL4-mediated mechanism by which TLRs cause autoimmunity in human B cells, breaching bone marrow tolerance.
TLR9 ligand sequestration by chemokine CXCL4 negatively affects central B cell tolerance
Authors: Elif Çakan, Marie Dominique Ah Kioon, Yolanda Garcia-Carmona, Salomé Glauzy, David Oliver, Natsuko Yamakawa, Andrea Vega Loza, Yong Du, Jean-Nicolas Schickel, Joshua M. Boeckers, Chao Yang, Alessia Baldo, Lionel B. Ivashkiv, Ryan M. Young, Louis M. Staudt, Krishna L. Moody, Kerstin Nündel, Ann Marshak-Rothstein, Caspar I. van der Made, Alexander Hoischen, Anthony Hayward, Marzia Rossato, Timothy R.D.J. Radstake, Charlotte Cunningham-Rundles, Changwan Ryu, Erica L. Herzog, Franck J. Barrat, Eric Meffre
Journal: The Journal of Experimental Medicine (2023)

Central B cell tolerance is believed to be regulated by B cell receptor signaling induced by the recognition of self-antigens in immature B cells. Using humanized mice with defective MyD88, TLR7, or TLR9 expression, we demonstrate that TLR9/MYD88 are required for central B cell tolerance and the removal of developing autoreactive clones. We also show that CXCL4, a chemokine involved in systemic sclerosis (SSc), abrogates TLR9 function in B cells by sequestering TLR9 ligands away from the endosomal compartments where this receptor resides. The in vivo production of CXCL4 thereby impedes both TLR9 responses in B cells and the establishment of central B cell tolerance. We conclude that TLR9 plays an essential early tolerogenic function required for the establishment of central B cell tolerance and that correcting defective TLR9 function in B cells from SSc patients may represent a novel therapeutic strategy to restore B cell tolerance.